The overall goal of this project is to develop a thromboresistant, small diameter prosthetic arterial graft for use in the clinical setting. Currently, there are no acceptable prostheses which can be utilized for vascular repair or replacement in situations which require a conduit with an internal diameter of less than 4mm due to prompt thrombosis. The objectives accomplished in the phase I proposal were: 1) development and characterization of a poly(carbonate urea) polyurethane with protein conjugation sites. 2) covalent linkage of the potent, thrombin-specific anticoagulant recombinant hirudin (rHir) to the modified biomaterial. 3) characterization of the rHir surface under static and flow conditions and 4) preliminary in vivo assessment of a rHir coated biomaterial. The goal of this phase II application, incorporating the promising in vitro and in vivo results obtained in phase I is to evaluate the in vivo performance of this system as a thromboresistant interface between blood and a small diameter (4mm) polyurethane vascular graft. The polyurethane with protein conjugation sites developed in phase I will be coated onto the luminal surfaces of pre-existing poly(carbonate urea) urethane vascular grafts by a proprietary spray head in the form of a coating. This coating will see as the foundation to which rHir will be covalently bound using the cross-linking technology developed in phase I. Physical properties such as tensile strength, water permeability and radial/longitudinal compliance of this novel vascular graft will be evaluated The graft surface will also be analyzed via Fournier transforming infra-red (FTIR) spectroscopy for chemical characterization and by scanning electron microscopy for porosity assessment. Control and rHir graft surface thromboresistance will be evaluated in vivo at various time intervals using a bilateral carotid artery grafting model in canines. Graft patency will be evaluated via color Duplex ultrasonography and blood samples will be drawn to evaluate changes in blood coagulation and 125 I-rHir release from the graft surface. Residual antithrombin activity of surface bound rHir post explanation will also be evaluated utilizing the chromogenic substrate assay. Standard histological analysis in conjunction with scanning electron microscopy will be employed to evaluate the surface morphology after explanation. The universal benefit of this research would be creating a clinically acceptable thromboresistant. small diameter prosthetic vascular graft. Optimization of this technology would also be relevant to other implantable biomaterials increasing their biocompatibility and opening new alternatives for their application. Commercially, development of a small-diameter thromboresistant vascular graft could result in a graft market of over $700 million annually. PROPOSED COMMERCIAL APPLICATIONS: A major untapped market exists for a thromboresistant synthetic small-diameter (4mm) vascular graft. Currently, there are no clinically acceptable biomaterials which can be utilized for small-diameter vessel repair or replacement. Development of such a graft could yield an annual $700 million graft market.